Patent EP-2145871-A1 (EP)
Inventor: PEGLION JEAN-LOUIS
IPC: C07F7/18
Filed: 2009-07-16
Abstract: Preparing a bicyclo[4.2.0]octa-1(6),2,4-triene compound (IV) comprises: cyclization reaction of an ethyl-benzene compound (V) in the presence of a catalyst/ligand comprising a palladium catalyst and an organic phosphine (including tri-tert-butyl phosphine, 2-biphenyl-di-tert-butylphosphine, 1,2,3,4,5-pentaphenyl-1'-(di-tert-butylphosphino)ferrocene and tris(4-methoxy-2-methylphenyl)phosphine, or phosphonium salt such phosphine, a base in an organic solvent), base and organic solvent. Preparing a bicyclo[4.2.0]octa-1(6),2,4-triene compound of formula (IV) comprises: cyclization reaction of an ethyl-benzene compound of formula (V) in the presence of a catalyst/ligand comprising a palladium catalyst and an organic phosphine (including tri-tert-butyl phosphine, 2-biphenyl-di-tert-butylphosphine, 1,2,3,4,5-pentaphenyl-1'-(di-tert-butylphosphino)ferrocene and tris(4-methoxy-2-methylphenyl)phosphine, or phosphonium salt such phosphine, a base in an organic solvent), base and organic solvent. Either R 1-R 4 : H, 1-6C alkyl, 1-6C alkoxy, F, Cl, protected amine group, protected hydroxyl group, 1-6C alkoxycarbonyl group, or CF 3; or R 1, R 4 : H; or CR 2R 3 : 1,3-dioxolane; R 5 : 1-6C alkyl, optionally saturated, 1-6C hydroxyalkyl (which hydroxyl function is protected), or CO 2R 7; R 7 : 1-6C alkyl; R 6 : CN or CO 2R 8; R 8 : 1-6C alkyl; and X : halo (preferably Br) or triflate group. Independent claims are included for: (1) a process for preparing bicyclo[4.2.0]octa-triene-7-carboxylic acid methyl ester compounds of formula (VIIa) comprising converting an ethyl-benzene compound (V) (where R 5 is CO 2R 7 and R 6 is CO 2R 8) into bicyclo[4.2.0]octa-1(6),2,4-triene compound (IV) (where R 5 is CO 2R 7 and R 6 is CO 2R 8); and converting (IV) by a reaction of hydrolysis or saponification of ester into a bicyclo[4.2.0]octa-1(6),2,4-triene-7,7-dicarboxylic acid methyl ester compound of formula (VIa); and decarboxylating (VIa) to give (VIIa); (2) bicyclo[4.2.0]octa-1(6),2,4-triene compound (IV) (where R 5 is CO 2R 7 and R 6 is CO 2R 8); (3) 3,4-dimethoxy-bicyclo[4.2.0]octa-1(6),2,4-triene-7,7-dicarboxylic acid methyl ester compound of formula (VIb); (4) 3,4-dimethoxy-bicyclo[4.2.0]octa-1(6),2,4-triene-7-carboxylic acid methyl ester compound of formula (VIIc); and (5) a process for preparing ivabradine (I) and its salts or hydrates comprising: converting ethyl-benzene compound (V) (where R 1 and R 4 is H, R 2 and R 3 is OCH 3, R 5 is CO 2R 7 and R 6 is CO 2R 8) in to 3,4-dimethoxy-bicyclo[4.2.0]octa-1(6),2,4-triene-7-carboxylic acid methyl ester compound (VIIc); reacting (VIIc) with methylamine to obtain 3,4-dimethoxy-bicyclo[4.2.0]octa-1(6),2,4-triene-7-carboxylic acid methylamide (VIII); reducing (VIII) to give (3,4-dimethoxy-bicyclo[4.2.0]octa-1(6),2,4-trien-7-ylmethyl)-methyl-amine (III); resolution of (III) in the presence of camphosulfonic acid to give 1-[(8S)-3,4-dimethoxy-8-bicyclo[4.2.0]octa-1(6),2,4-trienyl]-N-methyl-methanamine (II); and converting (II) into (I), which can be converted into its addition salts with acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, acetic acid, trifluoroacetic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, tartaric acid, maleic acid, citric acid, ascorbic acid, oxalic acid, methanesulfonic acid, benzenesulfonic acid and camphoric acid, or their hydrates. R 9, R 10 : 1-6C alkyl. [Image] [Image] [Image] ACTIVITY : Cardiant; Vasotropic; Antianginal; Antiarrhythmic. MECHANISM OF ACTION : None given.